Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with an EGFR inhibitor

ABSTRACT

A pharmaceutical composition of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof in combination with N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

FIELD OF THE INVENTION

This invention relates to a pharmaceutical composition for cancerdisease, which comprises a compound having anti-cancer activity, namely3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel pharmaceuticalcompositions having valuable properties, in particular those which canbe used for the preparation of medicaments.

Moreover, aim of this invention are new compositions for the preventionand treatment of neoplastic malignancies including, but without beinglimited to, solid tumor cancers, cancers of the lymphatic or bloodsystem.

It has been found that the pharmaceutical compositions according to theinvention and pharmaceutically acceptable salts and/or solvates thereofhave very valuable pharmacological properties while being welltolerated.

Most selective target therapies are when applied as single agents onlyeffective in highly addicted subpopulation of patients. By combiningselective target therapies with other targeted agents the anti tumoreffect can be enhanced by interfering with cross-talking pathways,blocking different tumor-specific pathways in parallel, or inhibitingthe same tumor-specific pathway at different levels to prevent or reducethe risk of progression.

PRIOR ART

3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehas been described in WO 2009/006959 A1.

3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate has been described in WO 2009/007074 A1.

N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide

is an EGFR inhibitor and has been described in WO 2012/061299.

The compound is useful in the treatment of hyperproliferative diseases,such as cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of an example concerning the combination of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamidein the human NSCLC HCC827-GR-T790M xenograft model.

FIG. 2 shows the results of an example concerning the combination of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamidein a human DFCI081 patient derived NSCLC xenograft (PDX)model.

SUMMARY OF THE INVENTION

The invention relates to a pharmaceutical composition of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to a pharmaceutical composition of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in combination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to a pharmaceutical composition of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamidefor the use for the treatment of diseases selected from the group cancerof the head, neck, eye, mouth, throat, esophagus, bronchus, larynx,pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinarybladder, uterine, cervix, breast, ovaries, testicles or otherreproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver,pancreas, brain, central nervous system, solid tumors and blood-bornetumors.

Moreover, the invention relates to a pharmaceutical composition of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in combination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamidefor the use for the treatment of cancer, selected from the group smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamouscell cancer of the head and neck (SCCHN).

Moreover, the invention relates to3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof for the usefor the treatment of cancer, wherein the medicament is to be used incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to the use of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof for themanufacture of a medicament for the treatment of cancer, wherein themedicament is to be used in combination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to the use of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate for the manufacture of a medicament for thetreatment of cancer, wherein the medicament is to be used in combinationwithN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to the use of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate for the manufacture of a medicament for thetreatment of cancer, selected from the group colorectal, lung, breast,kidney, and glioblastomas, wherein the medicament is to be used incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to the use of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate for the manufacture of a medicament for thetreatment of lung cancer, wherein the medicament is to be used incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to the use of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate for the manufacture of a medicament for thetreatment of cancer, selected from the group small cell lung cancer(SCLC), non-small cell lung cancer (NSCLC), squamous cell cancer of thehead and neck (SCCHN), wherein the medicament is to be used incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

Moreover, the invention relates to the use as described above, wherein3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof or3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is administered to a patient in an amount of 250mg to 12500 mg per week, preferably in an amount of 800 mg to 8000 mgper week, particularly preferably in an amount of 500 mg to 2000 mg perweek.

According to the present invention therapeutically active compositionsmay also be provided by means of a pharmaceutical kit comprising apackage comprising3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof, andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide,in single packages or in separate containers.

The therapy with these combinations may include optionally furthertreatment with radiation. The invention relates furthermore to a newtherapy form comprising the start of the administration of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof prior toradiotherapy.

In this new therapy form comprising the start of the administration of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof prior toradiotherapy, it is a preferred feature that the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof isadministered prior and/or during the administration ofN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide,preferably at least during a significant part of the treatment regimen.In this context, according to the present invention, radiation, or,radiotherapy preferably has to be understood as a cancer co-therapeuticagent.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

The invention also relates to the solvates of the salts of the compoundssuch as the mono- or dihydrate of the hydrochloride.

The term solvates of the compounds is taken to mean adductions of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are such as mono- or dihydrates oralcoholates.

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the inventionare for the most part prepared by conventional methods. If the compoundof the invention contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the invention are likewise included. In the case ofcertain compounds of the invention, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzene-sulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds include the following: acetate, adipate,alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate,caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate,glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,isethionate, isobutyrate, lactate, lactobionate, malate, maleate,malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds which are derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethyl-aminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds are prepared by bringing thefree base form into contact with a sufficient amount of the desiredacid, causing the formation of the salt in a conventional manner. Thefree base can be regenerated by bringing the salt form into contact witha base and isolating the free base in a conventional manner. The freebase forms differ in a certain respect from the corresponding salt formsthereof with respect to certain physical properties, such as solubilityin polar solvents; for the purposes of the invention, however, the saltsotherwise correspond to the respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds are formed with metals or amines, such as alkali metals andalkaline earth metals or organic amines. Preferred metals are sodium,potassium, magnesium and calcium. Preferred organic amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the invention inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound and/or pharmaceutically acceptable salts, solvates, tautomersand stereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethyl-cellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds and salts, solvates, tautomers and stereoisomers thereofcan also be administered in the form of liposome delivery systems, suchas, for example, small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds and the salts, solvates, tautomers and stereoisomersthereof can also be delivered using monoclonal antibodies as individualcarriers to which the compound molecules are coupled. The compounds canalso be coupled to soluble polymers as targeted medicament carriers.Such polymers may encompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound depends on a number offactors, including, for example, the age and weight of the animal, theprecise condition that requires treatment, and its severity, the natureof the formulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound according to the invention is generally in the range from0.1 to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as a single dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt, solvate, tautomer and stereoisomer thereof can be determined asthe fraction of the effective amount of the compound according to theinvention per se. It can be assumed that similar doses are suitable forthe treatment of other conditions mentioned above.

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the composition of the invention,conventional surgery or radiotherapy.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a subject at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with a compound can mean anamount capable of alleviating, in whole or in part, symptoms associatedwith a disorder or disease, or slowing or halting further progression orworsening of those symptoms, or preventing or providing prophylaxis forthe disease or disorder in a subject having or at risk for developing adisease disclosed herein, such as cancer,

The term “therapeutically effective” or “therapeutically effectiveamount” refers to an amount of a drug effective to treat a disease ordisorder in a mammal. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can, for example, bemeasured by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

Preferably, the compounds are administered once a week, preferablyintravenously as infusion. Preferably the initial dose is 100 to 1000 mgper m² body surface, particurlarly preferably between 200 and 600 mg perm² body surface. Subsequent doses are 50 to 600 mg per m² body surface,particurlarly preferably between 100 and 400 mg per m² body surface.

Particularly preferablyN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered orally in a tablettwice a day and3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is administered orally in a tablet once a day.More preferably, the two compounds are administered at the same timeorally.

Preferably, 3N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideis administered to a patient once or twice a day in an amount of 300 to900 mg per administration, more preferably in an amount of 400 to 800 mgper administration.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of immunemodulatory and stress response kinase-induced diseases. These diseasesinclude neoplastic malignancies including, but without being limited to,solid tumor cancers, cancers of the lymphatic or blood system, theproliferation of tumour cells, pathological neovascularisation (orangiogenesis) which promotes the growth of solid tumours,neurodegenerative diseases (Alzheimer, demyelinating core disordersmultiple sclerosis and the like), immune related disorders likearthritis, psoriasis, lupus, or other autoimmune diseases as well aschronic infections.

The present invention encompasses the use of the compounds and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of cancer.Preferred carcinomas for the treatment originate from the group cerebralcarcinoma, urogenital tract carcinoma, carcinoma of the lymphaticsystem, stomach carcinoma, laryngeal carcinoma and lung carcinoma. Afurther group of preferred forms of cancer are monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, melanomas and breast carcinoma. A further group ofpreferred forms of cancer include, but is not limited to, cervicalcancer, neuroblastoma, testicular cancer, macroglobulinemia andsarcomas.

The present invention specifically relates to compounds andpharmaceutically acceptable salts, solvates, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of neoplastic malignancies (solid tumor cancers, cancers ofthe lymphatic or blood system and the like), of neurodegenerativediseases, immune related disorders like arthritis, psoriasis, lupus,multiple sclerosis or other autoimmune diseases as well as chronicinfections.

Especial preference is given to the use for the treatment of a diseasewhere the disease is a neoplastic malignancies.

The neoplastic malignancies is preferably selected from the group oftumours of the lung, squamous epithelium, the bladder, the stomach, thekidneys, of head and neck, the esophagus, the cervix, the thyroid, theintestine, the liver, the brain, the prostate, the urogenital tract, thelymphatic system, the stomach and/or the larynx.

The neoplastic malignancies is furthermore preferably selected from thegroup lung adenocarcinoma, small-cell lung carcinomas, pancreaticcancer, glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of aneoplastic malignancies of the blood and immune system, preferably forthe treatment of a tumour selected from the group of acute myeloidleukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/orchronic lymphatic leukaemia.

Representative cancers that compounds are useful for treating orpreventing include, but are not limited to, cancer of the head, neck,eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone,lung, colon, rectum, stomach, prostate, urinary bladder, uterine,cervix, breast, ovaries, testicles or other reproductive organs, skin,thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, centralnervous system, solid tumors and blood-borne tumors.

Moreover, the present invention specifically relates to compounds forthe use for the treatment and/or prevention of cancer, where the cancerto be treated is a solid tumour or a tumour of the blood and immunesystem.

Moreover, the present invention specifically relates to compounds, forthe use for the treatment and/or prevention of cancer, where the wherethe tumour originates from the group of acute myeloid leukaemia, chronicmyeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphaticleukaemia.

Moreover, the present invention specifically relates to compounds, forthe use for the treatment and/or prevention of cancer, where the solidtumour originates from the group of tumours of the epithelium, thebladder, the stomach, the kidneys, of head and neck, the esophagus, thecervix, the thyroid, the intestine, the liver, the brain, the prostate,the uro-genital tract, the lymphatic system, the stomach, the larynx,the bones, including chondosarcoma and Ewing sarcoma, germ cells,including embryonal tissue tumours, and/or the lung, from the group ofmonocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas,pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breastcarcinoma and /or maligna melanoma.

The disclosed compounds of can be administered in combination with otherknown therapeutic agents, including anticancer agents. As used here, theterm “anticancer agent” relates to any agent which is administered to apatient with cancer for the purposes of treating the cancer.

Demonstration that by combining3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate with a third generation EGFR inhibitor,N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide,the efficacy ofN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamidecan be improved in lung cancer models, regardless of the EGFR T790Mstatus. Evaluation of the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloridehydrate/N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamidecombination in EGFR T790M mutant model further demonstrated not onlyenhanced activity compared toN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamidebut as well compared to3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate. The enhanced efficacy in the combination groupwas observed without increase in toxicity as indicated by the lack ofsignificant weight loss or death of animals compared to monotherapies.

Combination of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamidein the human NSCLC HCC827-GR-T790M xenograft model:

Background: The human NSCLC HCC827-GR-T790M is a EGFR del 19 mutant andc-Met amplified lung xenograft model which exogenous expression of theEGFR T790M resistant mutation. This model is resistant to EGFRinhibitors erlotinib and afatinib due to the acquired resistance throughc-Met amplification and the EGFR T790M mutation.

Method: Female NCr nude mice (7 weeks old) where subcutaneously injectedwith human HCC827-GR-T790M tumor cells and were divided into treatmentgroups (10 animals per group) after the tumors were established.Respective groups were administered orally with the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate (100 mg/kg) orN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide(100 mg/kg) daily in monotherapy or in combination until group tumorvolume mean reached 300 mm³ or up to 32 days. Median tumor volume (TV)change in % were calculated at day 14, where the vehicle group wasterminated and statistical analysis done with two way-RM ANOVA.

Results: Under3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamidemonotherapy treatment tumors progressed resulting in a median tumorvolume change of 205% (p<0.01) and 81% (p<0.0001), respectively.Combination of both agents statistically significant enhanced anti-tumoractivity compared to best single agentN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideresulting in complete tumor regression (median TV change of −87%,p<0.0001) in all mice. After long term combination treatment up to 32days, non-palpable tumors were observed in 5 out of 8 mice. (Tumorprogression: median TV change >73%; tumor stasis/regression: median TVchange <73%; complete tumor regression: non palpable tumors or tumorvolume <20 mm³ compared to start tumor volume.) Monotherapies andcombination treatment have been tolerated well. Results are shown inFIG. 1.

Combination of3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamidein a human DFCI081 patient derived NSCLC xenograft (PDX)model:

Background: The human DFCI081 NSCLC xenograft is a EGFR del 19 mutantand c-Met amplified lung tumor and resistant to EGFR inhibitorserlotinib and afatinib due to the activated c-Met pathway.

Method: Female NCr nude mice (7 weeks old) where subcutaneously injectedwith human DFCI081 tumor cells and were divided into treatment groups(10 animals per group) after the tumors were established. Respectivegroups were administered orally with the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate (100 mg/kg) orN-[3-[[24-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide(100 mg/kg) daily in monotherapy or in combination up to 18 days. Mediantumor volume (TV) change in % were calculated and statistical analysisdone with two way-RM ANOVA.

Results:3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate showed strong anti-tumor activity resulting intumor regression (TV change of −100%, p<0.0001). Complete tumorregression in all mice has been observed at day 15. Under treatment withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide,tumor progressed resulting in a median tumor volume change of 700% (ns).Combination of both agents did not statistically significant enhancedanti-tumor activity compared to best single agent3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate but complete tumor response in the combinationgroup has been induced in all mice earlier at day 11. (Tumorprogression: median TV change>73%; tumor stasis/regression: median TVchange<73%; complete tumor regression: non palpable tumors or tumorvolume<20mm³ compared to start tumor volume.) Monotherapies andcombination treatment have been tolerated well. Results are shown inFIG. 2.

The invention claimed is:
 1. A method for treating non-small cell lungcancer, comprising administering to a subject in need thereof aneffective synergistic amount of a pharmaceutical composition comprising3-(1-{3[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.2. The method according to claim 1, comprising administering to asubject in need thereof an effective amount of a pharmaceuticalcomposition comprising3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloridehydrate andN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.3. The method according to claim 1, wherein the 3N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideis administered once or twice a day in an amount of 300 to 900 mg peradministrationin.
 4. The method according to claim 1, wherein the 3N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideis administered once or twice a day in an amount of 300 to 900 mg peradministration and the3-(1-{3-[5-(1Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt thereof and/or solvate thereof isadministered in an amount of 250 mg to 12500 mg per week.
 5. The methodaccording to claim 2, wherein the 3N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideis administered once or twice a day in an amount of 300 to 900 mg peradministration and the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is administered in an amount of 250 mg to 12500 mgper week.
 6. The method according to claim 1, wherein the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof incombination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideis administered in a synergistic amount.
 7. The method according toclaim 1, wherein the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt and/or solvate thereof isadministered in an amount of 250 mg to 12500 mg per week.
 8. The methodaccording to claim 2, wherein the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate is administered in an amount of 250 mg to 12500 mgper week.
 9. The method according to claim 2, wherein the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrilehydrochloride hydrate in combination withN-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamideis administered in a synergistic amount.
 10. The method according toclaim 1, wherein the3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrileor a pharmaceutically acceptable salt thereof is administered in anamount of 250 mg to 12500 mg per week.